Identification Des Nouveaux Progrès Sur Les Molécules Dérivées Du Pyrazole Comme AgentsAntimicrobiens Et Antifongiques

Microbial infections remain a worldwide leading cause of death,despite the evolution of a large number of new antibiotics everyyear. Currently, several bacteria have developed resistanceagainst antibiotics drugs which remain a major issue inantibiotics drug discovery. This review provides detailedinformation about antimicrobial and antifungal agent synthesisbelonging to the pyrazoles scaffold. We reassemble the resultsobtained from several studies to characterize the importance ofheteroatom nuclei in many synthetic products. Additionally,several compounds based on pyrazole derivatives such asbenzimidazole, benzothiazole, indole, acridine, oxadiazole,imidazole, isoxazole, pyrazole, triazole, quinoline and quinazolineincluding other pyrazole containing drugs such as pyridazine,pyridine and pyrimidine are highlighted. Furthermore, you willfind in this review 134 best promise structures collected fromrecent studies, relating the pyrazoles structures to the relevantbiological activities, in particular, antimicrobial and antifungalone.

A tautomeric ligand enables directed C‒H hydroxylation with molecular oxygen.

Hydroxylation of aryl carbon-hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon-hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.

Synthesis of Some New Folic Acid-Based Heterocycles of Anticipated Biological Activity.

To date, no fused heterocycles have been formed on folic acid molecules; for this reason, and others, our target is to synthesize new derivatives of folic acid as isolated or fused systems. Folic acid 1 reacted with ethyl pyruvate, triethyl orthoformate, ethyl chloroformate, thioformic acid hydrazide, and aldehydes to give new derivatives of folic acid 2-6a,b. Moreover, It reacted with benzylidene malononitrile, acetylacetone, ninhydrin, ethyl acetoacetate, ethyl cyanoacetate, and ethyl chloroacetate to give the pteridine fused systems 10-15, respectively. Ethoxycarbonylamino derivate 5 reacted with some nucleophiles containing the NH2 group, such as aminoguanidinium hydrocarbonate, hydrazine hydrate, glycine, thioformic acid hydrazide, and sulfa drugs in different conditions to give the urea derivatives 16-20a,b. Compound 4 reacted with the same nucleophiles to give the methylidene amino derivatives 21-24a,b. The fused compound 10 reacted with thioglycolic acid carbon disulfide, malononitrile, and formamide to give the four cyclic fused systems 25-30, respectively. The biological activity of some synthesized showed moderate effect against bacteria, but no effect shown towards fungi.

Biotransformation of ß-Mangostin by an Endophytic Fungus of Garcinia mangostana to Furnish Xanthenes with an Unprecedented Heterocyclic Skeleton.

Biotransformation of ß-mangostin (1) by the endophytic fungus Xylaria feejeensis GM06 afforded hexacyclic ring-fused xanthenes with an unprecedented hexacyclic heterocylic skeleton. ß-Mangostin (1) was transformed to two diastereomeric pairs of enantiomers, mangostafeejin A [(-)-2a/(+)-2b)] and mangostafeejin B [(-)-3a/(+)-3b)]. The chemical structures of the transformation products were elucidated by analysis of NMR and MS data, and the structure of mangostafeejin A [(-)-2a/(+)-2b)] was confirmed by single-crystal X-ray diffraction analysis. The absolute configurations of 3a and 3b were established on the basis of calculated and measured ECD data using the ECD spectra of 2a and 2b as models. The fungal biotransformation described herein provides an effective method to convert an abundant achiral plant natural product scaffold into new chiral heterocyclic scaffolds representing expanded chemical diversity for biological activity screening.

Mesoporous silicas templated by heterocyclic amino acid derivatives: Biomimetic synthesis and drug release application.

The present paper reported a biomimetic synthesis of mesoporous silicas (BMSs) at room temperature by using synthesized polymers (C16-l-His, C16-l-Pro and C16-l-Trp) which derived from amino acid with ring structures as template under basic condition via co-structural-directing-agent method. The formation mechanism of BMSs and effect of initial synthesis conditions (such as surfactant structure, pH and co-solvents) on morphology and structure of BMSs were systematically studied. Synthesized BMSs were characterized by transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and nitrogen adsorption/desorption isotherms. The results showed that the surfactant structure was the dominant factor to direct the final mesostructure of BMSs, since the structure of surfactant affected the structure and size of clusters. Meanwhile the generation of BMSs required very rigorous alkaline condition which controlled the ionization degree of the surfactant and thus contributing to adequate stacking energy. Higher pH resulted in construction of channels with higher curvature. The presence of ethanol was found to facilitate the formation of BMSs with larger particle size. In application, aspirin can be loaded into BMSs with high efficiency, and the drug crystalline state of aspirin transformed from crystalline state to amorphous state during this process, which undoubtedly lead to the improvement of drug dissolution from 72.8% to 100% within 90 min. It is convincible that the biomimetic method presented here provided novel insight on precisely control of mesoporous silica and undoubtedly promoted the application of mesoporous silica materials.

Ruthenium(η6,η¹-arene-CH2-NHC) Catalysts for Direct Arylation of 2-Phenylpyridine with (Hetero)Aryl Chlorides in Water.

A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N-CH2-arene group. The benzimidazolium halides were readily converted into ruthenium(II)-NHC complexes with the general formula [RuCl2(η6,η¹-arene-CH2-NHC)]. The structures of all new compounds were characterized by ¹H NMR (Nuclear Magnetic Resonance), 13C NMR, FT-IR (Fourier Transform Infrared) spectroscopy and elemental analysis techniques. The single crystal structure of one benzimidazole ruthenium complex, 2b, was determined. The complex is best thought of as containing an octahedrally coordinated Ru center with the arene residue occupying three sites, the remaining sites being occupied by a (carbene)C-Ru bond and two Ru-Cl bonds. The catalytic activity of [RuCl2(η6,η¹-arene-CH2-NHC)] complexes was evaluated in the direct (hetero)arylation of 2-phenylpyridine with (hetero)aryl chlorides in water as the nontoxic reaction medium. These results show that catalysts 2a and 2b were the best for monoarylation with simple phenyl and tolyl chlorides. For functional aryl chlorides, 2d, 2e, and 2c appeared to be the most efficient.

Enantiospecific Solvolytic Functionalization of Bromochlorides.

Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.

Ruthenium-NHC-Diamine Catalyzed Enantioselective Hydrogenation of Isocoumarins.

A novel and practical chiral ruthenium-NHC-diamine system is disclosed for the enantioselective hydrogenation of isocoumarins, which provides a new concept to apply (chiral) NHC ligands in asymmetric catalysis. A variety of optically active 3-substituted 3,4-dihydroisocoumarins were obtained in excellent enantioselectivities (up to 99% ee). Moreover, this methodology was utilized in the synthesis of O-methylmellein, mellein, and ochratoxin A.

Activation of GPR119 Stimulates Human ß-Cell Replication and Neogenesis in Humanized Mice with Functional Human Islets.

Using humanized mice with functional human islets, we investigated whether activating GPR119 by PSN632408, a small molecular agonist, can stimulate human ß-cell regeneration in vivo. Human islets were transplanted under the left kidney capsule of immunodeficient mice with streptozotocin- (STZ-) induced diabetes. The recipient mice were treated with PSN632408 or vehicle and BrdU daily. Human islet graft function in the mice was evaluated by nonfasting glucose levels, oral glucose tolerance, and removal of the grafts. Immunostaining for insulin, glucagon, and BrdU or Ki67 was performed in islet grafts to evaluate α- and ß-cell replication. Insulin and CK19 immunostaining was performed to evaluate ß-cell neogenesis. Four weeks after human islet transplantation, 71% of PSN632408-treated mice achieved normoglycaemia compared with 24% of vehicle-treated mice. Also, oral glucose tolerance was significantly improved in the PSN632408-treated mice. PSN632408 treatment significantly increased both human α- and ß-cell areas in islet grafts and stimulated α- and ß-cell replication. In addition, ß-cell neogenesis was induced from pancreatic duct cells in the islet grafts. Our results demonstrated that activation of GPR119 increases ß-cell mass by stimulating human ß-cell replication and neogenesis. Therefore, GPR119 activators may qualify as therapeutic agents to increase human ß-cell mass in patients with diabetes.

Sulforaphane Analogues with Heterocyclic Moieties: Syntheses and Inhibitory Activities against Cancer Cell Lines.

Recent studies have shown that sulforaphane (SFN) selectively inhibits the growth of ALDH⁺ breast cancer stem-like cells.Herein, a series of SFN analogues were synthesized and evaluated against breast cancer cell lines MCF-7 and SUM-159, and the leukemia stem cell-like cell line KG-1a. These SFN analogues were characterized by the replacement of the methyl group with heterocyclic moieties, and the replacement of the sulfoxide group with sulfide or sulfone. A growth inhibitory assay indicated that the tetrazole analogs 3d, 8d and 9d were significantly more potent than SFN against the three cancer cell lines. Compound 14c, the water soluble derivative of tetrazole sulfide 3d, demonstrated higher potency against KG-1a cell line than 3d. SFN, 3d and 14c significantly induced the activation of caspase-3, and reduced the ALDH⁺ subpopulation in the SUM159 cell line, while the marketed drug doxrubicin(DOX) increased the ALDH⁺ subpopulation.

A review of experimental models in colorectal carcinogenesis / Modelos experimentais de carcinogênese colorretal

Colorectal cancer is the leading cause of malignancy of the gastrointestinal tract. A better understanding of the molecular and cellular changes that lead to the disease is necessary to develop early diagnosis and optimal treatment modalities. Rodent models are rapid, reproducible and exhibit an adenoma-carcinoma sequence similar to that found in humans. The objective of this manuscript is to review the most common chemical carcinogens used to induce experimental tumors and the usual methods of evaluation.

O câncer colorretal é a principal neoplasia maligna do trato gastrointestinal. Um melhor entendimento dos processos moleculares e celulares é necessário para o desenvolvimento de estratégias que permitam um diagnóstico precoce e um tratamento mais eficaz. Modelos que utilizam roedores são rápidos, reprodutíveis e permitem o estudo da sequencia adenoma-carcinoma de forma similar a encontrada em humanos. O objetivo desse manuscrito é revisar os principais modelos de carcinogênese química e os métodos mais usuais para avaliação dos resultados.

A Sustainable Approach to the Stereoselective Synthesis of Diazaheptacyclic Cage Systems Based on a Multicomponent Strategy in an Ionic Liquid.

The microwave-assisted three-component reactions of 3,5-bis(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones, acenaphthenequinone and cyclic α-amino acids in an ionic liquid, 1-butyl-3-methylimidazolium bromide, occurred through a domino sequence affording structurally intriguing diazaheptacyclic cage-like compounds in excellent yields.

SYNTHESIS AND STUDY OF HALOGENATED BENZYLAMIDES OF SOME ISOCYCLIC AND HETEROCYCLIC ACIDS AS POTENTIAL ANTICONVULSANTS.

A series of potential anticonvulsants have been synthesized. There are eight fluorobenzylamides and three chlorobenzylamides of isocyclic or heterocyclic acids. Two not halogenated benzylamides were also synthesized to compare the effect of halogenation. The aim of the research performed was to evaluate whether halogenation of the mother structure is able to improve its anticonvulsant activity. The compounds were tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Compound 1 showed MES ED50 = 80.32 mg/kg, PI = 3.16. Compound 7 showed CKM ED50 = 56.72 mg/kg. Compound 8 showed MES ED50 = 34.23 mg/kg and scPTZ ED50 > 300 mg/kg, PI = 8.53.Compound 13 showed 6Hz ED50 = 78.96, PI = 3.37. The results indicate that fluorination does not improve activity, whereas chlorination in our experiment even reduces it.

Impact of Precursors Creatine, Creatinine, and Glucose on the Formation of Heterocyclic Aromatic Amines in Grilled Patties of Various Animal Species.

The impact of precursors such as creatine, creatinine, and glucose on the formation of mutagenic/carcinogenic heterocyclic amines (HAs) were studied in patties of 9 different animal species equally heat treated with a double-plate contact grill. All grilled patties of the various species (veal, beef, pork, lamb, horse, venison, turkey, chicken, ostrich) contained several HAs such as MeIQx (2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline; 0.5-1.4 ng/g), 4,8-DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f] quinoxaline, 0 to 1.3 ng/g), PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine, 1.2 to 10.5 ng/g), harman (1-methyl-9H-pyrido[3,4-b] indole; 0.5 to 3.2 ng/g), and/or norharman (9H-pyrido[3,4-b]indole 0.5 to 1.9 ng/g). Residual glycogen (glucose) content varied greatly from 0.07 to 1.46 wt% on a dry matter (DM) basis. Total creatin(in)e content in raw meat (1.36 to 2.0 wt% DM) hardly differed between species, except in turkey and ostrich (1.1 wt% DM). Chicken contained, compared to all other species, very low concentrations of glucose (0.07 wt% DM) and the highest levels of nonprotein nitrogen compounds. The free amino acids lysine (r = 0.77, P < 0.001), tyrosine, phenylalanine, proline, isoleucine, and aspartic acid (r = 0.47-0.56, P < 0.05) showed significant correlation to PhIP in chicken. Also a linear correlation was found to exist between PhIP (r = 0.87, P < 0.001) and MeIQx (r = 0.35, P < 0.01), and the molar ratio of creatin(in)e to glucose, respectively. Harman as co-mutagens was linearly correlated to the concentration of glucose (r = 0.65, P < 0.001). By contrast, norharman was not significant correlated to glucose levels.

Thiophene, Selenophene, and Tellurophene-based Three-Dimensional Organic Frameworks.

3D frameworks are important because of their potential to combine the advantageous properties of porous materials with those associated with polymers. A series of novel 3D aromatic frameworks are presented that incorporate the heterocycles thiophene, selenophene, and tellurophene. The specific surface area and pore width of frameworks depends on the element that is used to build the framework. Optoelectronic properties are element-dependent, with heavy atoms red-shifting the optical properties and decreasing the energy gap of the solid. The metalloid nature of tellurophene allows the properties of this material to be tuned based on its oxidation state, even as an insoluble solid. The incorporation of the optoelectronic active thiophene, selenophene, and tellurophene units and the effect that they have on properties was studied. A supercapcitor device was fabricated using these frameworks, showing that these 3D frameworks are promising for optoelectronic uses.

Noncovalent Lone Pair⋠⋠⋠(No-π!)-Heteroarene Interactions: The Janus-Faced Hydroxy Group.

A comparative study using NMR spectroscopy and designed top-pan molecular balances demonstrates that the noncovalent interaction of a hydroxy group with π-deficient pyrazine and quinoxaline units involves a lone pair-heteroarene interaction which is much stronger and solvent independent when measured relative to the classical π-facial hydrogen bond to a benzene ring. Alkyl fluorides also prefer the heteroarene rings over the benzene ring. The attractive interaction between a quinoxaline and a terminal alkyne is also stronger than the intramolecular hydrogen bond to an arene.

Zinc-Catalyzed Alkyne Oxidation/C-H Functionalization: Highly Site-Selective Synthesis of Versatile Isoquinolones and ß-Carbolines.

An efficient zinc(II)-catalyzed alkyne oxidation/C-H functionalization sequence was developed, thus leading to highly site-selective synthesis of a variety of isoquinolones and ß-carbolines. Importantly, in contrast to the well-established gold-catalyzed intermolecular alkyne oxidation, over-oxidation can be completely suppressed in this system and the reaction most likely proceeds by a Friedel-Crafts-type pathway. Mechanistic studies and theoretical calculations are described.

Organocatalytic Asymmetric 1,6-Addition/1,4-Addition Sequence to 2,4-Dienals for the Synthesis of Chiral Chromans.

A novel asymmetric organocatalytic 1,6-addition/1,4-addition sequence to 2,4-dienals is described. Based on a 1,6-Friedel-Crafts/1,4-oxa-Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium-ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94-99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies.

Catalytic asymmetric synthesis of enantioenriched heterocycles bearing a C-CF3 stereogenic center.

Given the important agricultural and medicinal application of optically pure heterocycles bearing a trifluoromethyl group at the stereogenic carbon center in the heterocyclic framework, the exploration of efficient and practical synthetic strategies to such types of molecules remains highly desirable. Catalytic enantioselective synthesis has one clear advantage that it is more cost-effective than other synthetic methods, but remains limited by challenges in achieving excellent yield and stereoselectivities with a low catalyst loading. Thus far, numerous models of organo- and organometal-catalyzed asymmetric reactions have been exploited to achieve this elusive goal over the past decade. This review article describes recent progress on this research topic, and focuses on an understanding of the catalytic asymmetric protocols exemplified in the catalytic enantioselective synthesis of a wide range of complex enantioenriched trifluoromethylated heterocycles.

Direct activation of the proposed anti-diabetic receptor, GPR119 in cardiomyoblasts decreases markers of muscle metabolic activity.

GPR119 agonists are emerging rapidly as a pharmaceutical treatment of diabetes. Diabetes is a known risk factor for cardiovascular disease yet the cardiac-specific consequences of GPR119 activation are unknown. This study demonstrated that GPR119 agonism in cardiac myoblasts reduces metabolic activity in high and low concentrations of fatty acids, with high concentrations of palmitate largely attenuating the effects of the GPR119 agonist, PSN632408. The effects of GPR119 activation on gene and protein markers of metabolism were dependent on fatty acid exposure. Activating GPR119 did not affect cell hypertrophy of lipid accumulation regardless of lipid exposure. These results suggest that the pathways activated in response to GPR119 modulation in cardiac muscle cells differ between healthy and metabolically dysregulated states. However regardless of the pathway activated by GPR119, these effects may cause detrimental reductions to oxidative/metabolic capacity under both conditions. Thus further development of GPR119 agonists for treating metabolic diseases is warranted.